Sexual Dimorphism of Skeletal Muscle

骨骼肌的性别二态性

• 批准号: 8003643
• 负责人: VIRGINIA H HUXLEY
• 金额: $ 20.91万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003643
• 关键词: Abdomen; Abdominal Muscles; Acetylcholine; Acute; Address; Adenosine; Age; Animals; Atrial Natriuretic Factor; Behavior; Biochemical; Blood; Blood Vessels; Blood capillaries; Blood flow; Caliber; Cardiovascular Diseases; Data; Disease; Disease susceptibility; Disodium Salt Nitroprusside; Dose; Endothelin; Endothelium; Excision; Exposure to; Female; Fiber; Foundations; Functional disorder; Future; Genes; Genetic; Gonadal Steroid Hormones; Health; Human; Hypertension; In Situ; Incidence; Isoproterenol; Knowledge; Learning; Life; Liquid substance; Measures; Metabolic; Microcirculation; Modeling; Movement; Mus; Muscle; Muscle Contraction; Muscle function; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; Oxygen; Perfusion; Permeability; Pharmacology; Physiological; Preparation; Process; Property; Proteins; Regulation; Relaxation; Respiratory Transport; Rodent; Secondary to; Severities; Sex Characteristics; Signal Transduction; Skeletal Muscle; Study models; Testis; Tissues; Vascular Diseases; Vascular blood supply; abdominal wall; arteriole; capillary; cremaster muscle; data exchange; in vivo; intravital microscopy; macromolecule; male; model development; prevent; public health relevance; respiratory gas; response; response to injury; sex; sexual dimorphism; solute; treatment strategy; vasoactive agent; venule; wasting

DESCRIPTION (provided by applicant): Skeletal muscle (SKM) microvasculature has been studied extensively with respect to respiratory gas and nutrient exchange, volume distribution, and blood flow control, into and within the organ, in health and disease. This R21 is in response to a PFA requesting development of models for the study of function in males and females. This is terribly important as most studies of SKM have been conducted in males (animals and humans) with the presumption that the data apply equally to both sexes. Evidence from multiple studies accumulated over the last decade is making it clear that this assumption in error. One model used widely for in vivo study is the rodent cremaster, a thin muscle derived from the abdominal wall that raises and lowers the testes. Surprisingly, no microvascular skeletal muscle preparation of equivalent metabolic and fiber type substitutes presently for the cremaster that facilitates study of both males and females. This proposal aims to rectify this lack by validating the abdominal wall skeletal muscle preparation in males and female rodents. The hypothesis is that microvascular skeletal muscle functions do not differ between age-matched males and females of the same species. Accordingly, 3 aims will be carried out in in situ and isolated abdominal muscle microvessels from age- and strain-matched female and male mice: Aim 1 will assess whether sexual dimorphism exists with respect to blood flow regulation from measures from microvascular diameter to selected endothelium-dependent and -independent agents. Given recent data we expect to reject our hypothesis as we anticipate that a) arterioles from males will develop greater basal tone and b) the dose-response relationship for the endothelium-dependent dilation will differ between males and females. Aim 2 will assess whether sexual dimorphism exists with respect to exchange regulation from measures from measures of microvessel solute permeability (Ps). Given our data, we expect to reject our hypothesis as we anticipate that a) venules from males will be leakier than those from females, b) basal arteriole and capillary barrier properties will not differ by sex, and c) the vasoactive agents will produce a variety of exchange responses reflecting differences in sex-specific mechanisms regulating solute distribution between the vascular and tissue compartments of males and females. Aim 3 will compare the sex, age, organ and species matched diameter (Aim 1) and exchange data (Aim 2) from microvessels as they lay in the living tissue and following isolation from the tissue. This is an incredibly opportunity to make these comparisons as not all tissues are amenable to study in situ and it is assumed that the data from the isolated vessels reflect the behavior in the tissue. Data from this project will form the foundation for future genetic, biochemical, and physiologic studies of microvascular function in males and females. It is imperative that we validate a model for study of microvascular function in both sexes to understand intelligently the sex-dependent mechanisms regulating vascular function in health and dysfunction in disease. With the knowledge the foundation, and provide rational means for prevent and treating vascular disease specific to the needs of males and females.) PUBLIC HEALTH RELEVANCE: This project is to develop and validate a skeletal muscle model for the study of the primary functions of the smallest blood vessels in age-matched male and female animals of the same species, the mouse. The 2 primary functions of the microcirculation 1) blood flow to metabolizing tissue, and 2) the movement of nutrients from blood to tissue as well as the removal of wastes from tissue to blood, appear to differ between males and females in health and cardiovascular disease including hypertension and secondary to type 2 diabetes. As materials distribute themselves between blood and tissue, so too will fluids move between compartments; thus if exchange regulation differs between males and females it is likely that volume distribution will also differ. Therefore it is imperative to have access to a model to learn the differences and similarities between the sexes as the data from males, disease incidence and severity and subsequent treatment strategies will not apply equally to females.

描述（由申请人提供）：骨骼肌（SKM）微脉管系统已经广泛研究了呼吸气和营养交换，体积分布和血流控制，在器官中，健康和疾病中。该R21是对PFA的响应，该PFA要求开发男性和女性功能的模型。这非常重要，因为大多数SKM研究都是在男性（动物和人类）中进行的，并认为数据同样适用于两性。在过去十年中积累的多项研究的证据表明，这一假设是错误的。一个广泛用于体内研究的模型是啮齿动物Cremaster，这是一种源自腹壁的细肌肉，可抬高并降低睾丸。令人惊讶的是，目前，没有针对男性和雌性研究的Cremaster的等效代谢和纤维类型的微血管骨骼肌制备。该建议旨在通过验证男性和雌性啮齿动物的腹壁骨骼肌肉制备来纠正这种缺乏。假设是微血管骨骼肌功能在同一物种的年龄匹配的男性和女性之间没有差异。因此，将在原位进行3个目标，并从年龄和应变匹配的雌性和男性小鼠中进行孤立的腹部肌肉微血管：AIM 1将评估是否存在从微血管直径到选定的内皮依赖于依赖和依赖于 - 独立的和 - 独立的患者的血液流量调节的性二态性。鉴于最新数据，我们期望拒绝我们的假设，因为我们预计a）雄性的小动脉将发展出更大的基础语调，b）男性和女性之间依赖内皮依赖性扩张的剂量反应关系将有所不同。 AIM 2将评估从微血管溶质通透性（PS）的措施中进行的性二态性。鉴于我们的数据，我们期望拒绝我们的假设，因为我们预计a）a）男性的静脉比女性的静脉漏出，b）基础动脉和毛细血管屏障的特性不会因性别而差异，并且c）血管活性药物会产生各种反映性溶质机制和调节性质机制的差异的反应。 AIM 3将比较性，年龄，器官和物种匹配的直径（AIM 1），并从微血管中交换数据（AIM 2），因为它们躺在活组织中并与组织分离后。这是一个非常难以置信的机会进行这些比较，因为并非所有组织都可以原位研究，并且假定来自分离的血管的数据反映了组织中的行为。该项目的数据将构成男性和女性微血管功能的未来遗传，生化和生理研究的基础。我们必须验证两个男女微血管功能的模型，以明智地了解调节疾病健康和功能障碍血管功能的性依赖性机制。借助知识，基础，并提供了预防和治疗男性和女性需求特有的血管疾病的合理手段。） 公共卫生相关性：该项目是为了研究同一物种的年龄匹配的男性和雌性动物的最小血管的主要功能，以研究和验证骨骼肌模型。微循环的2个主要功能1）血液流向代谢组织，以及2）营养物质从血液到组织的运动以及从组织到血液的废物清除，男性和女性在健康和心血管疾病中的男性和女性之间似乎有所不同。当材料在血液和组织之间分布时，流体在隔间之间也会移动。因此，如果男性和女性之间的交换调节有所不同，则体积分布可能也会有所不同。因此，必须访问模型来学习性别之间的差异和相似性，因为男性的数据，疾病发生率和严重程度以及随后的治疗策略将不同样适用于女性。